An unsolved problem in cardiology is how to provide relief for patients with severe atherosclerotic coronary disease, in whom conventional revascularization techniques (i.e., angioplasty, bypass surgery) are not feasible. This situation arises (not uncommonly) when all three major coronary arteries are diseased along the majority of their length. Our Laboratory is interested in the application of angiogenic therapy to this problem, that is, enhancement of coronary collateral blood flow via the pharmacologic induction of blood vessel growth. We have developed a canine model whereby angiogenesis can be directed to ameliorate myocardial ischemia. The left anterior descending coronary artery (LAD) was occluded gradually over a 2 week period by placing an ameroid constrictor around the artery. At the same setting, the internal mammary artery (IMA) was implanted into the region supplied by the LAD. We have previously demonstrated that collaterals develop between the IMA and the territory normally perfumed by the LAD in this model, supplying nutritive collateral blood flow. By positioning a tube in the distal IMA, we were able to provide a continuous retrograde infusion directly into the vessel from an implanted pump, at the point where collaterals would develop between the IMA and the coronary circulation. Heparin, 15 or 150 units/hr, or saline vehicle alone were infused into the IMA. After 8 weeks, the IMA provided a greater proportion of maximal collateral flow in heparin treated dogs (23+-5%, N-16) than in saline treated dogs (10+-3%, N=12, p<0.05). Thus, in a preparation where collaterals are established between an extracardiac artery and the coronary circulation, angiogenic agents can be targeted locally by means of a continuous infusion at the anastomotic site, and administration of heparin in this preparation promotes the formation of collaterals between the extracardiac artery and the coronary circulation. In an ongoing experiment, we are attempting to determine whether heparin exerts a similar collateral-promoting effect when given systemically (by repeated subcutaneous injections) rather than locally.